Process for the production of cannabinoids

ABSTRACT

A process for the preparation of substantially pure diverse known and novel cannabinoids 1 and 2, which include Δ9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogues, via intermediates 3, 6, 4 and 5, using a cascade sequence of allylic rearrangement, aromatization and, for the tetracyclic cannabinoids, further highly stereoselective and regioselective cyclization. These synthesized cannabinoids can more easily be obtained at high purity levels than cannabinoids isolated or synthesized via known methods. The cannabinoids 2, including Δ9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), are obtained containing very low levels of isomeric cannabinoids such as the undesirable Δ8-tetrahydrocannabinol. The known and novel analogues with variation in aromatic ring substituents, whilst easily synthesized with the new methodology, would be much more difficult to make from any of the components of cannabis or cannabis oil.

FIELD OF THE INVENTION

The field of the invention relates to methods for the synthesis of high purity known and novel cannabinoids including but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring cannabinoids and other synthetic analogues from simple inexpensive starting materials by construction of the aromatic core. The field of the invention additionally covers novel cannabinoids, which may be used as active compounds either alone or admixed in combination with known cannabinoids and/or other drugs in drug formulations for the treatment of pain, multiple sclerosis-related spasticity, nausea, anorexia, epilepsy, Alzheimer's and neurodegenerative diseases, brain injury/concussion/traumatic brain injury, stroke, cancer, reduction of inflammation and immuno-inflammation related diseases, diseases/injury of the eye including but not limited to glaucoma, dry eye, corneal injury or disease and retinal degeneration or disease, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, pancreatitis and disorders of the pancreas cardiovascular injury or disease, and organ transplant, reduction of post-surgical inflammation among other diseases, anti-oxidants and indications.

BACKGROUND OF THE INVENTION

Cannabis (“marijuana”) is a plant of considerable notoriety and use particularly for the species Cannabis sativa. Marijuana use as a recreational drug worldwide, has been and remains the subject of high interest and legal review in many countries of the world. There has been very considerable interest in the use of this plant and its extracts as ethnopharmaceuticals for millennia with reference even in Herodotus, (The Histories, Book IV, page 295, Penguin Books, Ltd., Middlesex (1972). The plant and its extracts have been and are used in medicine on account of their effects including as hypnotic agents, anti-anxiety agents, inflammation and immuno-inflammation regulatory agents, on pain including cancer pain, pain, neuropathic pain, spasmolytics, to combat the side effects of cancer chemotherapy including nausea, in the treatment of glaucoma, epilepsy and as appetite stimulant including for AIDS patients among other users.

There are over 60 constituent compounds that have been isolated and characterized from Cannabis sativa oil (for example see S. A. Ahmed, S. A. Ross, D. Slade, M. M. Radwan, F. Zulfiqar and M. A. ElSohly “Cannabinoid Ester Constituents from High-Potency Cannabis sativa”, Journal of Natural Products, 2008, volume 71, pages 536-542 and references therein). In addition, a considerable number of these natural products and analogs have been prepared by total synthesis from aromatic and monoterpene precursor compounds. Such total syntheses are reported (for examples see R. K. Razdan, “The Total Synthesis of Cannabinoids” in “The Total Synthesis of Natural Products”, Editor J. ApSimon, 1996, volume 4, pages 185-262, New York, N.Y.: Wiley and Sons; J. W. Huffman and J. A. H. Lainton, “Recent Developments in the Medicinal Chemistry of Cannabinoids”, Current Medicinal Chemistry, 1996, volume 3, pages 101-116; N. Itagaki, T. Sugahara and Y. Iwabuchi, “Expedient Synthesis of Potent Cannabinoid Receptor Agonist (−)-CP55,940”, Organic Letters, 2005, volume 7, pages 4181-4183; J. A. Teske and A. Deiters, “A Cyclotrimerization Route to Cannabinoids”, Organic Letters, 2008, volume 10, pages 2195-2198; S. Tchilibon and R. Mechoulam, “Synthesis of a Primary Metabolite of Cannabidiol”, Organic Letters, 2000, volume 2, pages 3301-3303; Y. Song, S. Hwang, P. Gong, D. Kim and S. Kim*, “Stereoselective Total Synthesis of (−)-Perrottetinene and Assignment of Its Absolute Configuration”, Organic Letters, 2008, volume 10, pages 269-271; Y. Kobayashi, A. Takeuchi and Y.-G. Wang, “Synthesis of Cannabidiols via Alkenylation of Cyclohexenyl Monoacetate”, Organic Letters, 2006, volume 8, pages 2699-2702; B. M. Trost and K. Dogra, “Synthesis of (−)-Δ⁹-trans-Tetrahydrocannabinol: Stereocontrol via Mo-Catalyzed Asymmetric Allylic Alkylation Reaction”, Organic Letters, 2007, volume 9, pages 861-863; L.-J. Cheng, J.-H. Xie, Y. Chen, L.-X. Wang and Q.-L. Zhou, “Enantioselective Total Synthesis of (−)-Δ⁸-THC and (−)-Δ⁹-THC via Catalytic Asymmetric Hydrogenation and S_(N)Ar Cyclization” Organic Letters, 2013, volume 15, pages 764-767; P. R. Nandaluru and G. J. Bodwell, “Multicomponent Synthesis of 6H-Dibenzo[b,d]pyran-6-ones and a Total Synthesis of Cannabinol”, Organic Letters, 2012, volume 14, pages 310-313; S. Ben-Shabat, L. O. Hanus, G. Katzavian and R. Gallily, “New Cannabidiol Derivatives: Synthesis, Binding to Cannabinoid Receptor, and Evaluation of Their Antiinflammatory Activity”, Journal of Medicinal Chemistry, 2006, volume 49, pages 1113-1117; A. Mahadevan, C. Siegel, B. R. Martin, M. E. Abood, I. Beletskaya and R. K. Razdan, “Novel Cannabinol Probes for CB1 and CB2 Cannabinoid Receptors”, Journal of Medicinal Chemistry, 2000, volume 43, pages 3778-3785; S. P. Nikas, S. O. Alapafuja, I. Papanastasiou, C. A. Paronis, V. G. Shukla, D. P. Papahatjis, A. L. Bowman, A. Halikhedkar, X. Han and A. Makriyannis, “Novel 1′,1′-Chain Substituted Hexahydrocannabinols: 9β-Hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist”, Journal of Medicinal Chemistry, 2010, volume 53, pages 6996-7010).

In the last twenty years it has become apparent that the cannabinoids are in a renaissance for diverse biomedical uses. The pharmacology of the cannabinoids has been shown to be associated with a number of receptors and mechanisms including cannabinoids receptors, GPCR receptors, serotonin receptors, modulation of several voltage-gated channels (including Ca²⁺, Na⁺, and various type of K⁺ channels), ligand-gated ion channels (i.e., GABA, glycine and TRPV), Toll like receptors, opioid receptors, NMDA or excitatory amino acids receptors, catecholamine receptors, enzymes regulating endocannabinoids, and ion-transporting membranes proteins such as transient potential receptor class (TRP) channels (L. De Petrocellis, M. Nabissi, G. Santoni and A. Ligresti, “Actions and Regulation of Ionotropic Cannabinoid Receptors”, Advances in Pharmacology, 2017, volume 80, pages 249-289; P. Morales and P. H. Reggio, “An Update on Non-CB₁, Non-CB₂ Cannabinoid Related G-Protein-Coupled Receptors”, Cannabis Cannabinoid Research, 2017, volume 2, pages 265-273). Thus, it would be helpful to have a new medicament or medicaments that include one or more cannabinoids for treatment of afflictions known to be treatable by affecting or using these physiological mechanisms.

Much of the work with cannabinoids have considered that its actions are for a number of indications includes directly or indirectly receptor-mediated effects by two G protein-coupled receptors, named CB₁ and CB₂, which have 44% sequence homology in humans. The CB₁ sub-type is the most widely expressed G protein-coupled receptor in the brain in regions, for example, that control motor, emotional, cognitive, sensory responses, perception of pain, thermoregulation, as well as cardiovascular, gastrointestinal, and respiratory physiology. It is localized in the central (CNS) and peripheral nervous systems including the olfactory bulb, cortical areas, parts of the basal ganglia, thalamus, hypothalamus, cerebellar cortex, brainstem, and spinal cord. CB₁ receptors also occur in cells in the pituitary and thyroid glands, some fat, muscle and liver cells as well as the lung and kidneys. The CB₂ sub-type is expressed in immune and hematopoietic cells, osteoclasts, and osteoblasts and mediates the response of the immune system, controls inflammation, modulates inflammatory and neuropathic pain as well as bone remodeling. Thus, it would be helpful to have a new medicament or medicaments for treatment of afflictions known to be treatable by affecting these physiological paths that includes one or more cannabinoids for preventing, treating or curing inflammatory mediated diseases or inflammatory mediated pathological conditions of one or more from the group consisting of the central or peripheral nervous system, cardiovascular-renal system, skin, gastrointestinal system, pulmonary-respiratory system, endocrine system, joints, musculo-skeletal system, blood or lymph system, genitourinary system, eye, and ear or for the prevention, treatment or cure of one or more of anorexia, arthritis, cancer, pain, glaucoma, migraine, persistent muscle spasms in an individual or animal in need of treatment and seizures.

The pharmacology of modulators of CB₁ and CB₂ receptors has been reviewed for example by Vemuri and Makriyannis (V. K. Vemuri and A. Makriyannis, “Medicinal Chemistry of Cannabinoids”, Clinical Pharmacology & Therapeutics, 2015, volume 97, pages 553-558). The psychoactive effects of Δ⁹-tetrahydrocannabinol (7) as well as with its primary metabolite 11-hydroxy-Δ⁹-tetrahydrocannabinol (8) are mediated by its partial agonism of CNS CB₁ receptors (J. van Amsterdam, T. Brunt and W. van den Brink, “The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects”, Journal of Psychopharmacology, 2015, volume 29, pages 254-263; R. G. Pertwee, “The diverse CB₁ and CB₂ receptor pharmacology of three plant cannabinoids: Δ⁹-tetrahydrocannabinol, cannabidiol and Δ⁹-tetrahydrocannabivarin”, British Journal of Pharmacology, 2008, volume 153, pages 199-215). It is useful as an analgesic, an antiemetic agent, and for treating anorexia in patients with AIDS. Other CB₁ receptor modulators include tetrahydrocannabivarin (9) (weak antagonist) and cannabinol (10) (weak agonist) and both are modest agonists of CB₂. Both the non-psychoactive (−)-cannabidiol (11) and cannabidivarin (12) do not interact significantly with either receptor sub-class and their modes of action are less clear (J. Fernández-Ruiz, O. Sagredo, M. R. Pazos, C. Garcia, R. Pertwee, R. Mechoulam, J. Martinez-Orgado, “Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?”, British Journal of Clinical Pharmacology, 2013, volume 75, pages 323-333; S. Rosenthaler, B. Pöhn, C. Kolmanz, C. N. Huu, C. Krewenka, A. Huber, B. Kranner, W.-D. Rausch and R. Moldzio, “Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures”, Neurotoxicology and Teratology, 2014, volume 46, pages 49-56). The combination of Δ⁹-tetrahydrocannabinol (7) and cannabidiol (11) (Sativex, Nabiximols) is used to treat multiple sclerosis-related spasticity and as a potent analgesic in patients with advanced stage cancers. More recently, purified cannabidiol (11) was granted orphan drug status for treating epilepsy. CB₁ receptor antagonists are appetite suppressants, enhance cognition, and control addictive behavior. Selective CB₂ agonists may provide superior analgesic agents and immunomodulators that do not have the undesirable psychoactive effects associated with CNS CB₁ agonism. Δ⁹-Tetrahydrocannabinol (7) (Dronabinol) has been shown to be clinically effective either in monotherapy or in combination with ondansetron (Zofran, a 5-HT₃ antagonists) and in combination with prochlorperazine (a dopamine D₂ receptor antagonist) to treat chemotherapy-induced nausea and vomiting in cancer patients (M. B. May and A. E Glode, “Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics”, Cancer Management and Research, 2016, volume 8, pages 49-55).

Cannabinoids that are used as therapeutics are currently either obtained from the fractionation of cannabis or cannabis oil or from total synthesis usually from aromatic and terpene starting materials. Since there are over 60 different natural products in cannabis and its oil, such fractionation requires extensive chromatographic purification to provide any individual constituent substantially pure and with so many components makes reproducible production and storage difficult. In the context of this patent application, substantially pure means at least 99% chemically (constitutionally, diastereoisomerically and enantiomerically) pure and additionally not contaminated with any agrochemicals including herbicides, fungicides and insecticides or any pathogens that may be associated with cannabinoids isolated from plant-derived cannabis oil. The purification of Δ⁹-tetrahydrocannabinol (7) from other cannabis constituents but particularly from its isomer Δ⁸-tetrahydrocannabinol is inefficient and costly. In addition, since many of the cannabinoids in cannabis oil have different effects as total, partial, inverse or neutral agonists or antagonists of either or both of the CB₁ and CB₂ receptors, it is especially important that individual isolated natural products do not contain significant levels (below parts per million levels) of any other cannabinoid natural product, which has undesired biological effects and that the specifications set are efficiently reproducible. There is an added complication in that many cannabinoid natural products are obtained as oils, which are typically not possible to crystallize and which are prone to air oxidative degradation and their isolation requires the use of extensive expensive and difficult to scale chromatography and/or derivatisation (for example see B. Trawick and M. H. Owens, “Process for the Preparation of (−)-delta 9-Tetrahydrocannabinol”, WO 2009/099868 A1; E. Arslantas and U. Weigl, “Method for Obtaining Pure Tetrahydrocannabinol”, U.S. Pat. No. 7,923,558 B2; J. E. Field, J. Oudenes, B. I. Gorin, R. Orprecio, F. E. Silva e Souza, N. J. Ramjit and E.-L. Moore, “Separation of Tetrahydrocannabinols”, U.S. Pat. No. 7,321,047 B2; P. Bhatarah, K. J. Batchelor, D. McHattie and A. K. Greenwood, “Delta 9 Tetrahydrocannabinol Derivatives”, WO 2008/099183 A1; D. C. Burdick, S. J. Collier, F. Jos, B. Biolatto, B. J. Paul, H. Meckler, M. A. Helle and A. J. Habershaw, “Process for Production of Delta-9-Tetrahydrocannabinol”, U.S. Pat. No. 7,674,922 B2). Secondly, many synthetic routes to prepare cannabinoids either use expensive reagents and are uneconomic to use on a large scale or are dependent on the condensation reactions of monoterpene starting materials with derivatives of alkyl-resorcinol such as 5-n-pentyl-resorcinol (olivetol) under acidic reaction conditions, reactions that frequently give rise to side products derived from carbenium ion rearrangement reactions and/or side reactions. For example, the manufacture of Δ⁹-tetrahydrocannabinol (7) from olivetol and monoterpenes by Brønsted or Lewis acid catalyzed condensation reactions is complicated by the co-formation of its isomer Δ⁸-tetrahydrocannabinol, amongst other impurities. Such impurities also considerably complicate and increase the cost of obtaining cannabinoid active pharmaceutical ingredients substantially pure (for examples see R. K. Razdan, “The Total Synthesis of Cannabinoids” in “The Total Synthesis of Natural Products”, Editor J. ApSimon, 1996, volume 4, pages 185-262, New York, N.Y.: Wiley and Sons; C. Steup and T. Herkenroth, “Process for Preparing Synthetic Cannabinoids”, US Patent Application 2010/0298579 A1; R. J. Kupper, “Cannabinoid Active Pharmaceutical Ingredient for Improved Dosage Forms”, WO 2006/133941 A2; J. Erler, and S. Heitner, “Method for the Preparation of Dronabinol”, U.S. Pat. No. 8,324,408 B2; A. L. Gutman, M. Etinger, I. Fedotev, R. Khanolkar, G. A. Nisnevich, B. Pertsikov, I. Rukhman and B. Tishin, “Methods for Purifying trans-(−)-Δ⁹-Tetrahydrocannabinol and trans-(+)-Δ⁹-Tetrahydrocannabinol”, U.S. Pat. No. 9,278,083 B2). The present invention is directed towards overcoming these problems and, as well as providing efficient/reproducible manufacturing routes for known cannabinoids, provides flexible syntheses of novel cannabinoids, which may be used as active compounds either alone or admixed in combination with known cannabinoids and/or other drugs in drug formulations for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, immune-inflammation mediated disorders, amongst other pathologies.

SUMMARY OF THE INVENTION

Among the benefits and improvements disclosed herein, other objects and advantages of the disclosed embodiments will become apparent from the following. Detailed embodiments of cannabinoid compounds, intermediary compounds, and a process for preparation of cannabinoid and cannabimimetic compounds and their intermediaries are disclosed; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention which are intended to be illustrative, and not restrictive.

Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrases “In some embodiments” and “in some embodiments” as used herein do not necessarily refer to the same embodiment(s), though it may. The phrases “in another embodiment” and “in some other embodiments” as used herein do not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments may be readily combined, without departing from the scope or spirit of the invention.

In addition, as used herein, the term “or” is an inclusive “or” operator, and is equivalent to the term “and/or,” unless the context clearly dictates otherwise. The term “based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a,” “an,” and “the” include plural references. The meaning of “in” includes “in” and “on.

Further, the terms “substantial,” “substantially,” “similar,” “similarly,” “analogous,” “analogously,” “approximate,” “approximately,” and any combination thereof mean that differences between compared features or characteristics is less than 25% of the respective values/magnitudes in which the compared features or characteristics are measured and/or defined.

As used herein, the term “substituted benzyl” means a benzyl ring bearing 1, 2 or 3 independently varied C1-C4 alkyl, C1-C4 alkyloxy, fluoro, chloro, hydroxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, cyano, or methoxymethyl groups at an aromatic ring position or 1 or 2 independently varied C1-C4 alkyl at the benzylic methylene.

As used herein, the term “optionally substituted aryl” means a phenyl ring optionally bearing 1, 2 or 3 independently varied C1-C4 alkyl, C1-C4 alkyloxy, fluoro, or chloro groups.

If not otherwise defined herein, the term “substituted” means optionally substituted at any position with varied C1-C4 alkyl, C1-C4 alkyloxy, fluoro, chloro, hydroxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, cyano, or methoxymethyl groups.

The present invention relates to a process for the preparation of diverse known and novel cannabinoids 1 and 2 from the novel precursors 3 or 6 or mixtures of 3 with 6 via the novel intermediates 4 as the racemic modifications, or as the specific enantiomers shown below or as the enantiomers of 1 or 2 including Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other known and novel synthetic tetracyclic and tricyclic analogues from simple inexpensive starting materials using a cascade sequence of allylic rearrangement, aromatization and, for the tetracyclic cannabinoids 2, highly stereoselective and regioselective further cyclization producing the Δ⁹-cannabinoids 2 largely free from the undesired Δ⁸-isomers.

wherein:

-   -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s) (s is         4, 5 or 6) with Rα and Rβ being preferably both methyl.

The present invention also relates to a related process for the preparation of novel intermediates of the formula 3 from reaction of the monoterpene starting materials 13 with the 1,3-dioxanediones 14 as the racemic modification or as mixtures of the two enantiomers in non-equal proportions, or as the specific enantiomer shown below or as the enantiomer of 3:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   Rγ is H, C₁ to C₆ alkyl and R⁶ is optionally substituted aryl;     -   s is 4, 5 or 6.

The present invention also relates to a related process for the preparation of novel intermediates of the formula 6 from reaction of the monoterpene starting materials 15 with the 1,3-dioxanediones 14 as the racemic modification or as mixtures of the two enantiomers in non-equal proportions, or as the specific enantiomer shown below or as the enantiomer of 6:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   Rγ is H, C₁ to C₆ alkyl and R⁶ is optionally substituted aryl;     -   s is 4, 5 or 6.

The synthetic methods are suitable for use on a large scale and for manufacturing purposes. Examples of known cannabinoids that are available using the synthetic routes are cannabidiol (11), cannabidivarin (12), Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9) and compounds related to Nabilone (16).

The synthetic methods are also suitable for the synthesis of other known and novel cannabinoids and these compounds are also part of the invention. The cannabinoids 1 below, which are novel analogs of cannabidiol (11) and cannabidivarin (12), are also available by the synthetic routes herein described and are part of the invention. These cannabinoids 1 have the formula:

-   -   wherein:     -   R¹ is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, C₃ to C₈         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;         R^(E) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; or NR^(D)R^(E) is         azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each         optionally substituted by one or two hydroxyl groups or         hydroxymethyl groups with the exception that the hydroxyl groups         cannot be on the carbon bearing the heterocyclic ring nitrogen         or the heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 1 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 1 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral, sublingual, intranasal, inhalation, rectal or parenteral drug administration or by other known methods of clinical administration.

The cannabinoids 1 below, which are also novel analogs of cannabidiol (11), cannabidivarin (12), are also available by the synthetic routes herein described and are part of the invention. These cannabinoids 1 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 1 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 1 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral, sublingual, intranasal, inhalation, rectal or parenteral drug administration or by other known methods of clinical administration.

The cannabinoids 1 below, which are novel analogs of cannabidiol (11), cannabidivarin (12), are also available by the synthetic routes herein described and are part of the invention. These cannabinoids 1 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, C₃ to C₆         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;         R^(E) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, C₃ to C₆         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;         or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or         piperidinyl each optionally substituted by one or two hydroxyl         groups or hydroxymethyl groups with the exception that the         hydroxyl groups cannot be on the carbon bearing the heterocyclic         ring nitrogen or the heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 1 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, eye injury or disease including glaucoma, dry eye and retinal degeneration, disorders of immune-inflammation, pain, side effects of chemotherapy, anxiety, lung injury or disease, liver injury or disease, kidney injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 1 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral, sublingual, intranasal, inhalation, topical, rectal or parenteral drug administration or by other known methods of clinical administration.

The dioxinone derivatives 3 below, which are intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 3 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is a hydroxyl protecting group, CH₃, CH₂CH₃, CH₂CH₂CH₃ or         CH(CH₃)₂;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

The dioxinone resorcylate derivatives 4 below, which are novel intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 4 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently is 0, 1, 2, 3, 4, 5 or 6;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

The cannabinoids 2 below, which are novel analogs of Δ⁹-tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), are also available by the synthetic routes herein described and are part of the invention. These cannabinoids 2 have the formula:

-   -   wherein     -   R¹ is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to a alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 2 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's and neurodegenerative diseases, brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 2 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral, sublingual, intranasal, inhalation, rectal or parenteral drug, transdermal administration or by other known methods of clinical administration.

The cannabinoids 2 below, which are novel analogs of Δ⁹-tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), are also available by the synthetic routes herein described and are part of the invention. These cannabinoids 2 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, C₃ to C₈ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; or NR^(D)R^(E) is         azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each         optionally substituted by one or two hydroxyl groups or         hydroxymethyl groups with the exception that the hydroxyl groups         cannot be on the carbon bearing the heterocyclic ring nitrogen         or the heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;

The aforementioned novel cannabinoids with the limited formulae 2 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 2 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral, sublingual, intranasal, inhalation, rectal or parenteral drug, transdermal administration or by other known methods of clinical administration.

The cannabinoids 2 below, which are also novel analogs of Δ⁹-tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), are also available by the synthetic routes herein described and are part of the invention. These cannabinoids 2 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, C₃ to C₆         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl.     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 2 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's and neurodegenerative diseases, brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 2 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral, sublingual, intranasal, inhalation, rectal or parenteral drug administration or by other known methods of clinical administration.

The dioxinone resorcylate derivatives 5 below, which are intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 5 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to a alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

The dioxinone derivatives 6 below, which are novel intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 6 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D show data for dose response and comparison in HEK-TRPV1 cells between Cannabidiol synthesized according to the disclosed embodiments to sourced “control” Cannabidiol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of diverse known and novel cannabinoids 1 and 2 as the racemic modifications, or as the specific enantiomers shown below or as the enantiomers of 1 or 2 including Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogues from simple inexpensive starting materials using a cascade sequence of allylic rearrangement, aromatization and, for the tetracyclic cannabinoids 2, highly stereoselective and regioselective further cyclization producing the Δ⁹-cannabinoids 2 largely free from the undesired Δ⁸-isomers. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

where:

-   -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to s alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;     -   said process comprising:     -   treating a first novel intermediate of the formula 3 in which         any hydroxyl group in R¹ and/or R² [wherein R² is (CH₂)_(m)—OH]         is protected sequentially with (1) an acylating reagent R^(B)COY         in which any hydroxyl group or groups in R^(B) are protected in         the presence of a first mild base 17 and also in the presence of         a mild Lewis acid 18, (2) a palladium catalyst 19 with optional         additional ligands 20 and (3) silica or an alternative         equivalent solid reagent or a second mild base 21 followed by a         Brønsted or Lewis acid 22 or a mild base alone such as cesium         acetate and optional deprotection to provide the novel second         intermediate 4 and secondly hydrolysis of said 4 with optional         decarboxylation or by transesterification or by amide formation         with optional deprotection as appropriate to provide 1;         wherein:     -   Y is a halogen preferably chlorine or R^(B)COY is an alternative         reactive electrophilic acylating agent;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s) (s is         4, 5 or 6) with Rα and Rβ being preferably both methyl;     -   the first mild base 17 is an amine or a heterocyclic amine such         as pyridine;     -   the mild Lewis acid 18 is preferably magnesium chloride;     -   the palladium catalyst 19 is either derived from a palladium(II)         precatalyst or its itself a palladium(0) catalyst and the         optional additional ligands 20 include but are not limited to         one or more phosphines or diphosphines or their equivalents,         preferably the palladium catalyst 19 and ligands 20 are         specifically but not limited to phosphine complexes of         palladium(0) such as tetrakis(triphenylphosphine)palladium(0) or         tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] in the         presence of a triarylphosphine or triheteroarylphosphine         particularly tri-2-furylphosphine; the second mild base 21 is         cesium acetate or cesium carbonate or potassium carbonate;     -   the Brønsted or Lewis acid 22, if used, is acetic acid or         hydrogen chloride.         wherein:     -   the optional hydroxyl-protecting group or groups are silyl         protecting groups;     -   the optional hydroxyl-protecting group or groups are preferably         independently t-butyldimethylsilyl, thexyldimethylsilyl,         t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

Protecting groups are well known to persons skilled in the art and are described in textbooks such as Greene and Wuts, (P. G. M. Wuts, T. W. Greene, “Greene's Protective Groups in Organic Synthesis”, 2006, Fourth Edition, John Wiley, New York).

Amide formation is carried out by activation of the carboxylic acid for example by formation of the N-hydroxysuccinimide ester and coupling with the corresponding amine, for example see Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, “Determination of tetrahydrocannabinolic acid—carrier protein conjugate by matrix-assisted laser desorption/ionization mass spectrometry and antibody formation”, Organic Mass Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include but are not limited to dicyclohexyl carbodiimide (DCC), di-iso-propyl carbodiimide (DIC), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 0-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, volume 38, pages 606-631).

The present invention also relates to a related process for the preparation of diverse known and novel cannabinoids 1 and 2 as the racemic modifications, or as the specific enantiomers shown below or as the enantiomers of 1 or 2 including Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic known and novel tetracyclic and tricyclic analogues from simple inexpensive starting materials using a cascade sequence of allylic rearrangement, aromatization and, for the tetracyclic cannabinoids, further cyclization. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

where:

-   -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;     -   said process comprising:     -   treating a first novel intermediate of the formula 6 in which         any hydroxyl group in R¹ and/or R² [wherein R² is (CH₂)_(m)—OH]         is protected sequentially with (1) an acylating reagent R^(B)COY         in which any hydroxyl group or groups in R^(B) are protected in         the presence of a first mild base 17 and also in the presence of         a mild Lewis acid 18, (2) a palladium catalyst 19 with optional         additional ligands 20 and (3) silica or an alternative         equivalent solid reagent or a second mild base 21 followed by a         Brønsted or Lewis acid 22 or a mild base alone such as cesium         acetate and optional deprotection to provide the second novel         intermediate 4 and secondly hydrolysis of said 4 with optional         decarboxylation or by transesterification or by amide formation         with optional deprotection as appropriate to provide 1;         wherein:     -   Y is halogen preferably chlorine or R^(B)COY is an alternative         reactive electrophilic acylating agent;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s) (s is         4, 5 or 6) with Rα and Rβ being preferably both methyl;     -   the first mild base 17 is an amine or a heterocyclic amine such         as pyridine;     -   the mild Lewis acid 18 is preferably magnesium chloride;     -   the palladium catalyst 19 is either derived from a palladium(II)         precatalyst or its itself a palladium(0) catalyst and the         optional additional ligands 20 include but are not limited to         one or more phosphines or diphosphines or their equivalents,         preferably the palladium catalyst 19 and ligands 20 are         specifically but not limited to phosphine complexes of         palladium(0) such as tetrakis(triphenylphosphine)palladium(0) or         tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] in the         presence of a triarylphosphine or triheteroarylphosphine         particularly tri-2-furylphosphine;     -   the second mild base 21 is cesium acetate or cesium carbonate or         potassium carbonate;     -   the Brønsted or Lewis acid 22, if used, is acetic acid or         hydrogen chloride.         wherein:     -   the optional hydroxyl-protecting group or groups are silyl         protecting groups;     -   the optional hydroxyl-protecting group or groups are preferably         independently t-butyldimethylsilyl, thexyldimethylsilyl,         t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

Protecting groups are well known to persons skilled in the art and are described in textbooks such as Greene and Wuts, (P. G. M. Wuts, T. W. Greene, “Greene's Protective Groups in Organic Synthesis”, 2006, Fourth Edition, John Wiley, New York).

Of particular note in the invention is that the method of linking the terpene unit to the aromatic ring in intermediate 4 ensures, as a result of the π-allyl-palladium mediated step, the position of the alkene unit in the cyclohexene ring unit is formed regiospecifically as depicted in structure 4 and no other isomers are formed to any significant extent (for a discussion of the mechanism see R. Cookson, T. N. Barrett and A. G. M. Barrett, “β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, volume 48, pages 628-642 and references therein).

Amide formation is carried out by activation of the carboxylic acid for example by formation of the N-hydroxysuccinimide ester and coupling with the corresponding amine, for example see Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, “Determination of tetrahydrocannabinolic acid—carrier protein conjugate by matrix-assisted laser desorption/ionization mass spectrometry and antibody formation”, Journal of Mass Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include but are not limited to dicyclohexyl carbodiimide (DCC), di-iso-propyl carbodiimide (DIC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, volume 38, pages 606-631).

The present invention also relates to a related process for the preparation of diverse known and novel cannabinoids 1 and 2 as the racemic modifications, or as the specific enantiomers shown below or as the enantiomers of 1 or 2 including Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogues from mixtures of the novel intermediates 3 and 6 simple inexpensive starting materials using a cascade sequence of allylic rearrangement, aromatization to produce the resorcylate derivatives 4 and, for the tetracyclic cannabinoids, further cyclization.

It should be noted that several of the intermediates in these syntheses can exist as keto- and enol tautomers. The depiction of a structure as a keto-form also includes the corresponding enol-form including mixtures containing both keto- and enol forms. Additionally, the depiction of a structure as an enol-form also includes the corresponding keto-form including mixtures containing both keto- and enol forms. By way of examples, intermediates 3 and 6 exist as mixtures of both keto- and enol forms although the structures, for reasons of simplicity, are drawn as the keto-forms. Additionally, it should be noted that whilst a structure is drawn as a particular stereoisomer and enantiomer, the invention also includes the enantiomeric compounds, racemic compounds and mixtures of the two enantiomers in non-equal proportions. Additionally, the invention also covers structurally feasible diastereoisomers. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

The present invention also relates to a related process for the preparation of diverse known and novel cannabinoids of the formula 2 as the racemic modification or as mixtures of the two enantiomers in non-equal proportions, or as the specific enantiomer shown below or as the enantiomer of 2:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆         cycloalkyl optionally substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6;     -   said process comprising:     -   treating a first novel intermediate of the formula 4 or the         cannabinoid 1 in which any hydroxyl group or groups in R¹, R²         [wherein R² is (CH₂)_(m)—OH] and/or R^(B) are protected with (1)         a Lewis acid 23 and secondly treating the resultant novel         intermediate 5 by hydrolysis with optional decarboxylation or by         transesterification or by amide formation with optional         deprotection as appropriate to provide 2;

wherein:

-   -   Rα and Rβ are both preferably methyl;     -   the Lewis acid 23 is a derivative of a metal or metalloid such         as but not limited to boron(III), aluminum(III), zinc(II),         tin(IV), titanium(IV), zirconium(IV), scandium(II), a         lanthanide(III) or bismuth(III) or an inorganic solid such as a         zeolite or an equivalent or is replaced by a Brønsted acid such         as but not limited to methanesulfonic acid, 4-toluenesulfonic         acid or hydrogen chloride or any combination of such a Lewis         acid and Brønsted acid, Lewis acid and inorganic solid; Brønsted         acid and inorganic solid or Lewis acid, Brønsted acid and         inorganic solid;     -   the Lewis acid 23 is alternatively a derivative of boron(III)         such as boron trifluoride or boron trifluoride etherate;     -   the Lewis acid 23 is alternatively a derivative of aluminum(III)         such as aluminum chloride, ethylaluminum dichloride or         diethylaluminum chloride;     -   the Lewis acid 23 is alternatively a derivative of zinc(II) such         as zinc chloride or zinc bromide;     -   the Lewis acid 23 is alternatively a derivative of tin(IV) such         as stannic chloride;     -   the Lewis acid 23 is alternatively a derivative of titanium(IV)         such as titanium tetrachloride or iso-propoxytitanium         trichloride;     -   the Lewis acid 23 is alternatively a derivative of zirconium(IV)         such as zirconium tetrachloride;     -   the Lewis acid 23 is alternatively a derivative of scandium(III)         such as scandium tris-trifluoromethanesulfonate or scandium         tris-(di-(trifluoromethanesulfonyl)amide or scandium         tris-(tri-(trifluoromethanesulfonyl)methide;     -   the Lewis acid 23 is alternatively a derivative of         lanthanide(III) such as ytterbium tris-trifluoromethanesulfonate         or ytterbium tris-(di-(trifluoromethanesulfonyl)amide or         ytterbium tris-(tri-(trifluoromethanesulfonyl)methide;     -   the Lewis acid 23 is alternatively a derivative of bismuth(III)         such as bismuth tris-trifluoromethanesulfonate or bismuth         tris-(di-(trifluoromethanesulfonyl)amide or bismuth         tris-(tri-(trifluoromethanesulfonyl)methide.         wherein:     -   the hydroxyl protecting group or groups are silyl protecting         groups;     -   the hydroxyl protecting group or groups are preferably         independently t-butyldimethylsilyl, thexyldimethylsilyl,         t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

Protecting groups are well known to persons skilled in the art and are described in textbooks such as Greene and Wuts, (P. G. M. Wuts, T. W. Greene, “Greene's Protective Groups in Organic Synthesis”, 2006, Fourth Edition, John Wiley, New York).

Amide formation is carried out by activation of the carboxylic acid for example by formation of the N-hydroxysuccinimide ester and coupling with the corresponding amine, for example see Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, “Determination of tetrahydrocannabinolic acid—carrier protein conjugate by matrix-assisted laser desorption/ionization mass spectrometry and antibody formation”, Journal of Mass Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include but are not limited to dicyclohexyl carbodiimide (DCC), di-iso-propyl carbodiimide (DIC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, “Amide bond formation: beyond the myth of coupling reagents”, Chemical Society Reviews, 2009, volume 38, pages 606-631).

The Lewis acid 23 mediated cyclization reactions of cannabinoids 4 to cannabinoids 5 is known for related compounds that lack this key RαRβC ketal unit such as in examples of the cannabinoids 1 and the extension of this reaction to compounds with this ketal unit is part of the invention. Such indirect precedent includes publications by Rhee, Childers, Gaoni, Adams, Glaser, Koch, Steup, Burdick, Kupper and Gutman (M.-H. Rhee, Z. Vogel, J. Barg, M. Bayewitch, R. Levy, L. Hanus, A. Breuer and R. Mechoulam, “Cannabinol Derivatives: Binding to Cannabinoid Receptors and Inhibition of Adenylylcyclase”, Journal of Medicinal Chemistry, 1997, volume 40, pages 3228-3233; W. E. Childers, Jr., H. W. Pinnick, “A Novel Approach to the Synthesis of the Cannabinoids”, Journal of Organic Chemistry, 1984, volume 49, pages 5276-5277; Y. Gaoni and R. Mechoulam “Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish”, The Journal of the American Chemical Society, 1964, volume 86, pages 1646-1647; R. Adams, D. C. Pease, C. K. Cain and J. H. Clark, “Structure of Cannabidiol. VI. Isomerization of Cannabidiol to Tetrahydrocannabinol, a Physiologically Active Product. Conversion of Cannabidiol to Cannabinol”, The Journal of the American Chemical Society, 1940, volume 62, pages 2402-2405; R. Glaser, I. Adin, R. Machoulam and L. Hanus, “2-Methyl- and 4-Methyl-Δ⁸-tetrahydrocannabinol: Correlation of Spatial Distinction with Cannabinoid Receptor Binding”, Heterocycles, 1994, volume 39, pages 867-877; O. Koch, M. R. Götz, J. Looft and T. Vössing, “Mixtures of cannabinoid compounds, and production and use thereof”, US Patent Application 2015/0336874 A1; C. Steup and T. Herkenroth, “Process for preparing synthetic cannabinoids”, US Patent Application 2010/298579 A1; D. C. Burdick, S. J. Collier, F. Jos, B. Biolatto, B. J. Paul, H. Meckler, M. A. Helle, A. J. Habershaw, “Process for production of delta-9-tetrahydrocannabinol”, U.S. Pat. No. 7,674,922 B2 (2010); R. J. Kupper, “Cannabinoid active pharmaceutical ingredient for improved dosage forms”, WO2006/133941 A2; J. Erler and S. Heitner, “Method for the production of Dronabinol from Cannabidiol, using a molecular sieve”, WO2006/136273 A1; A. L. Gutman, M. Etinger, I. Fedotev, R. Khanolkar, G. A. Nisnevich, B. Pertsikov, I. Rukhman and B. Tishin, “Methods for purifying trans-(−)-Δ⁹-tetrahydrocannabinol and trans-(+)-Δ⁹-tetrahydrocannabinol”, U.S. Pat. No. 9,278,083 B2). In consequence, hydrolysis with optional decarboxylation or by transesterification or by amide formation with optional deprotection as appropriate provides the Δ⁹-cannabinoids 2 with very low levels of the undesired Δ⁸-cannabinoids. The use of the RαRβC ketal unit to control the regioselectivity of reaction is inventive, however the mono-protection of cannabidiol as a methyl ether, generated in situ, was reported to be regiospecific for the synthesis of Δ⁹-tetrahydrocannabinol (7) (W. E. Childers, Jr. and H. W. Pinnick, “A Novel Approach to the Synthesis of the Cannabinoids”, The Journal of Organic Chemistry, 1984, volume 49, pages 5276-5277).

The present invention also relates to a related process for the preparation of novel intermediates of the formula 3 as the racemic modification or as mixtures of the two enantiomers in non-equal proportions, or as the specific enantiomer shown below or as the enantiomer of 3:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6;     -   said process comprising:     -   treating intermediate of the formula 13 in which any hydroxyl         group in R¹ and/or R² [wherein R² is (CH₂)_(m)—OH] is protected         with the mild acylating agent 14 in an inert solvent at a         temperature of 40 to 100° C. to produce intermediate 3 retaining         as appropriate said hydroxyl protecting group.

wherein:

-   -   the inert solvent is a halogenated solvent or an aromatic         hydrocarbon;     -   the inert solvent is preferably an aromatic hydrocarbon such as         toluene;     -   the temperature of reaction is preferably 40 to 60° C.;     -   preferably the temperature of reaction is 50° C. and the solvent         is toluene.         wherein:     -   the hydroxyl-protecting group or groups are silyl protecting         groups;     -   the hydroxyl-protecting group or groups are preferably         independently t-butyldimethylsilyl, thexyldimethylsilyl,         t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

Protecting groups are well known to persons skilled in the art and are described in textbooks such as Greene and Wuts, (P. G. M. Wuts, T. W. Greene, “Greene's Protective Groups in Organic Synthesis”, 2006, Fourth Edition, John Wiley, New York).

The present invention also relates to a related process for the preparation of novel intermediates of the formula 6 as the racemic modification or as mixtures of the two enantiomers in non-equal proportions, or as the specific enantiomer shown below or as the enantiomer of 6:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6;     -   said process comprising:     -   treating intermediate of the formula 15 in which any hydroxyl         group in R¹ and/or R² [wherein R² is (CH₂)_(m)—OH] is protected         with the mild acylating agent 14 in an inert solvent at a         temperature of 40 to 100° C. to produce the novel intermediate         6.

wherein:

-   -   the inert solvent is a halogenated solvent or an aromatic         hydrocarbon;     -   the inert solvent is preferably an aromatic hydrocarbon such as         toluene;     -   the temperature of reaction is preferably 40 to 60° C.;     -   preferably the temperature of reaction is 50° C. and the solvent         is toluene.         wherein:     -   the hydroxyl-protecting group or groups are silyl protecting         groups;     -   the hydroxyl-protecting group or groups are preferably         independently t-butyldimethylsilyl, thexyldimethylsilyl,         t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

Protecting groups are well known to persons skilled in the art and are described in textbooks such as Greene and Wuts, (P. G. M. Wuts, T. W. Greene, “Greene's Protective Groups in Organic Synthesis”, 2006, Fourth Edition, John Wiley, New York).

An example of the new method is given in Scheme 1 below. The keto-ester dioxinone 24 is synthesized from the keto-dioxinone 29 and imidazolide 30 or an equivalent reagent such as, but not limited to a benzotriazole carbonate derivative or a 4-nitrophenyl carbonate, using methods equivalent to those published for other related keto-ester dioxinones (R. Cookson, T. N. Barrett and A. G. M. Barrett, “β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, volume 48, pages 628-642 and references therein).

C-Acylation of keto-ester dioxinone 24 is carried out using hexanoyl chloride in the presence of a base such as pyridine in the presence of magnesium chloride to provide the corresponding adduct 25. This may be isolated and purified but, in a preferred embodiment, is taken directly to the next stage. Subsequent decarboxylation and allylic rearrangement using methods equivalent to those published for other related diketo-dioxinones (R. Cookson, T. N. Barrett and A. G. M. Barrett, “β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis”, Accounts of Chemical Research, 2015, volume 48, pages 628-642 and references therein) provides the corresponding β,δ-diketo-dioxinone 26 with the monoterpene unit attached at the α-carbon. Typical catalysts for the conversion of intermediate 25 into diketo-dioxinone 26 include palladium(0) catalysts, which may be already at the palladium(0) oxidation state such as Pd(PPh₃)₄ or as a palladium(II) pre-catalyst in the presence of a phosphine or equivalent monodentate or alternative bidentate or higher dentate ligands. Alternative metal catalysts may be employed for the conversion of 25 into 26 including but not limited to complexes of iron or molybdenum, which are known to a person skilled in the art to be of use in metal-catalyzed reactions that proceed via π-allyl metal intermediates.

Intermediate 26 may be isolated and purified but, in a preferred embodiment, is taken directly to the next stage without isolation. Reaction of the diketo-dioxinone 26 with a second catalyst such as silica gel or cesium carbonate followed by hydrochloric acid produces the resorcylate derivative 27. Alternative catalysts for this aromatization reaction are given in the Accounts of Chemical Research paper cited above. In the most preferred embodiment of the reaction, the keto-ester 24 is converted in a single vessel via intermediates 25 and 26 into the resorcylate 27 without any isolation and purification except for the product 27, a derivative of cannabidiol (11).

Cyclization of 27 using boron trifluoride etherate as reported in the synthesis of hongoquercin B (T. N. Barrett and A. G. M. Barrett, “Cascade Polyketide and Polyene Cyclizations: Biomimetic Total Synthesis of Hongoquercin B”, The Journal of the American Chemical Society, 2014, volume 136, pages 17013-17015) or with other Lewis or Brønsted acids or Lewis/Brønsted acid combinations well known to a person skilled in the art in the cannabinoid area provides the Δ¹-tetrahydrocannabinolic acid derivative 28.

Cleavage of the dioxinone rings of intermediate 28 by saponification or an equivalent process as described in the Accounts of Chemical Research paper cited above gives Δ¹-tetrahydrocannabinolic acid (31). Decarboxylation of Δ¹-tetrahydrocannabinolic acid (31) provides tetrahydrocannabinol (7) (see H. Perrotin-Brunel, W. Buijs, J. van Spronsen, M. J. E. van Roosmalen, C. J. Peters, R. Verpoorte and G.-J. Witkamp, “Decarboxylation of Δ⁹-tetrahydrocannabinol: Kinetics and molecular modeling”, Journal of Molecular Structure, 2011, volume 987, pages 67-73 and references therein). In the same way, saponification or an equivalent process and decarboxylation of intermediate 27 gives cannabidiol (11).

It additionally needs to be stressed that since the starting materials are pure, e.g. hexanoyl chloride contains no butanoyl chloride, the product cannabinoids with n-pentyl side chains, for example Δ⁹-tetrahydrocannabinol (7), are not contaminated by the corresponding cannabinoids with n-propyl side chains such as cannabidivarin (12) and tetrahydrocannabivarin (9). In addition, since the methods used for the link-up of the aromatic core to the terpene unit are so mild and regiospecific, the products are much easier to purify than those produced with classical synthetic routes, which may contain impurities derived from well-known monoterpene rearrangements as well as other contaminants.

It should be noted that the synthesis in Scheme 1 is carried out with equivalent starting materials. For example, the sequence is carried out starting with the terpene 32 with the protected 2-hydroxy-propyl group or alternative terpene compounds. In these cases, intermediates with the protected 2-hydroxy-propyl group corresponding to 30, 25, 26 and 27 as well as that corresponding to 11 also retain the same substituent.

It should be noted that the synthesis in Scheme 1 is carried out replacing hexanoyl chloride with butanoyl chloride as in Scheme 2. The steps directly parallel those in the earlier scheme and provide tetrahydrocannabivarin (9) and cannabidivarin (12) and the C-3 analogue of Δ¹-tetrahydrocannabinolic acid (31) above and rely upon the equivalent inventive steps.

It needs also to be stressed that since the starting materials are pure, e.g. butanoyl chloride contains no hexanoyl chloride, the product cannabinoids with n-propyl side chains are not contaminated by the corresponding cannabinoids with n-pentyl side chains such as cannabidiol (11) and Δ⁹-tetrahydrocannabinol (7). In addition, since the methods used for the link-up of the aromatic core to the terpene unit are so mild and regiospecific, the products are much easier to purify than those produced with classical synthetic routes, which may contain impurities derived from well-known monoterpene rearrangements as well as other contaminants. It also needs to be stressed the invention is that the use of the Me₂C ketal unit ensures that the cyclization reaction to produce the cannabinoid 36 provides only the Δ⁹-isomer and the undesired Δ⁸-isomer is not formed to any significant extent. In consequence, hydrolysis with decarboxylation provides tetrahydrocannabivarin (9) as the Δ⁹-isomer with very low levels of the undesired Δ⁸-isomer.

The methods of Schemes 1 and 2 are also of use for the concise synthesis of families of novel cannabinoids with hitherto unknown ring substituents from the C-acylation of dioxinone 37 with the carboxylic acyl chlorides 38, decarboxylative allylic rearrangement, aromatization and hydrolysis and decarboxylation. Examples of such novel cannabinoids include but are not limited to the analogues 39 and 40 (R¹=a C₂ to C₆ alkyl, cyclopropyl, phenyl with R²=n-pentyl) and (R¹=CH₃ with R²=cyclopropyl, cyclobutyl, cyclopentyl, phenyl) as well as “inverted” analogues 39 and 40 (R¹=n-pentyl, R²=CH₃). The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

The aforementioned novel cannabinoids with formulae 39 and 40 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with formulae 39 and 40 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, flavors and fragrances such as but not limited to the volatile terpenes of Cannabis and citrus fruits and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

In another embodiment of the invention the key intermediates for the decarboxylation, allylic rearrangement and aromatization steps are prepared using the methods shown in Schemes 3 and 4. Terpene allylic alcohol building blocks such as 41 or 44 undergo reaction with dioxanedione 14 under mild heating to give the corresponding dioxinone β-keto-esters, 42 or 45 respectively. In a preferred embodiment reaction is carried out with alcohol 41 or alcohol 44 with reagent 14 (Rα=Rβ=Rγ=methyl, Rδ=phenyl or Rα=Rβ=methyl, Rγ=H, Rδ=phenyl) at a temperature of between 50° C. and 60° C. However it should be noted that an alternative dioxanedione 14 may be used provided that the substituents Rα, Rβ, Rγ and Rδ are chosen such that addition of the terpene alcohol occurs at the dione moiety exclusively. For example, Rα and Rβ in combination can be (CH₂)_(n) (n=4, 5) with Rγ and Rδ both as methyl.

Dioxanedione 14 is prepared by coupling Meldrum's acid derivative 48 with carboxylic acid 47 and an appropriate activating agent such as (but not limited to) N,N′-dicyclohexyl carbodiimide (DCC) or an equivalent (see D. C. Elliott, T.-K. Ma, A. Selmani, R. Cookson, P. J. Parsons, and A. G. M. Barrett “Sequential Ketene Generation from Dioxane-4,6-dione-keto-dioxinones for the Synthesis of Terpenoid Resorcylates”, Organic Letters, 2016, volume 18, pages 1800 to 1803).

The C-acylation of compounds 42 or 45 are carried out with an appropriate acylating agent such as R^(B)COX where X=Cl, Br, OSO₂CF₃, etc. In a preferred embodiment hexanoyl chloride is used (X=Cl) and R^(B)=(CH₂)₄CH₃ in the presence of magnesium chloride and a base such as pyridine to give diketo-dioxinones 43 and 46 respectively. Preferably without further purification, the crude esters 43 and 46 either as separate compounds or as mixtures of these two regioisomers are subjected to the previously mentioned decarboxylation and allylic rearrangement via palladium catalysis to give the corresponding β,δ-diketo-dioxinones 49 with the monoterpene unit attached at specifically the γ-carbon as illustrated in Scheme 5. Typical catalysts for the conversion of intermediate 43 and 46 into diketo-dioxinone 49 include palladium(0) catalysts such as Pd₂dba₃ in the presence of a phosphine or equivalent monodentate ligand such as P(2-furyl)₃. Alternative catalysts may also be used by someone skilled in the art as previously discussed above.

Intermediate 49 is converted directly to the next stage intermediate preferably without isolation and purification. Thus reaction of the diketo-dioxinone 49 with a second catalyst such as cesium acetate produces the resorcylate derivative 50. Conversion of the resorcylate derivative 50 into intermediate 51 and cannabinoids such as 52 and 53 are carried out by methods as previously discussed above.

It should be noted that the synthesis in Schemes 3, 4 and 5 can be carried out with appropriate starting materials and reagents that permit the synthesis of analogs and families of cannabinoids including but not limited to cannabinoids 5, 54 and 55 starting from the monoterpene analogs 15 and/or 13 (or its enantiomer 56), condensation with the reagents 14, C-acylation of intermediates 6 and/or 3 (or its enantiomer 57) to produce the esters 58 and/or 59 (or their enantiomers) and subsequent decarboxylative allylic rearrangement and aromatization.

For example, the synthetic sequence which is carried out starting with the terpenes 41 and/or 44 in Schemes 3 and 4, may also be carried out with, but are not limited to, alternative monoterpene analogs 15 and/or 56 (R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₈ cycloalkyl, (CH₂)_(m)—OR³; R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, (CH₂)_(m)—OR³; n are independently 0, 1 or 2; m are independently 1 or 2; R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂). Furthermore, the C-acylation of keto dioxinones 42 and/or 45, or more generally 6 and/or 57, can be carried out with acylating agents to provide cannabinoids with different side chains on the aromatic ring. Examples include, but are not limited to natural side chains with R^(B)=n-propyl (cannabidivarin and tetrahydrocannabivarin families), R^(B)=n-pentyl(cannabidiol and tetrahydrocannabinol families) or unnatural side chains with R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl or double branched C₄ to C₁₀ alkyl in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally substituted by a C₁ to C₈ alkyl; and

-   -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;

The synthetic methods in Schemes 1, 2, 3, 4 and 5 are suitable for use on a large scale and for manufacturing purposes particularly since the key cyclization reactions in the invention do not give rise to unwanted isomeric side products. Examples of known cannabinoids that are available using the synthetic routes are cannabidiol (11), cannabidivarin (12), Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9) and compounds related to Nabilone (16). The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

The synthetic methods in Schemes 1, 2, 3, 4 and 5 are suitable for the synthesis of novel cannabinoids and these compounds are also part of the invention. The cannabinoids 1 below, which are novel analogs of cannabidiol (11) and cannabidivarin (12), are also available by the synthetic routes herein described and are part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs. These cannabinoids 1 have the formula:

-   -   wherein:     -   R¹ is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, C₃ to C₈         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;         R^(E) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; or NR^(D)R^(E) is         azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each         optionally substituted by one or two hydroxyl groups or         hydroxymethyl groups with the exception that the hydroxyl groups         cannot be on the carbon bearing the heterocyclic ring nitrogen         or the heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 1 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment or prevention of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 1 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

The cannabinoids 1 below, which are also novel analogs of cannabidiol (11) and cannabidivarin (12), are also available by the synthetic routes herein described and are part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs. These cannabinoids 1 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 1 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 1 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

The cannabinoids 1 below, which are novel analogs of cannabidiol (11) and cannabidivarin (12), are also available by the synthetic routes herein described and are part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs. These cannabinoids 1 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, C₃ to C₆         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;         R^(E) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, C₃ to C₆         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;         or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or         piperidinyl each optionally substituted by one or two hydroxyl         groups or hydroxymethyl groups with the exception that the         hydroxyl groups cannot be on the carbon bearing the heterocyclic         ring nitrogen or the heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;

The aforementioned novel cannabinoids with the limited formulae 1 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) Nabilone (16) or endocannabinoids and/or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 1 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

The dioxinone derivatives 3 below, which are novel intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 3 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is a hydroxyl protecting group, CH₃, CH₂CH₃, CH₂CH₂CH₃ or         CH(CH₃)₂;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

The novel dioxinone resorcylate derivatives 4 below, which are intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 4 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently is 0, 1, 2, 3, 4, 5 or 6;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

The cannabinoids 2 below, which are novel analogs of Δ⁹-tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), are also available by the synthetic routes herein described and are part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

These cannabinoids 2 have the formula:

-   -   wherein     -   R¹ is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 2 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) Nabilone (16) or endocannabinoids and/or other drugs for the treatment of prevention of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 2 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), endocannabinoids or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

The cannabinoids 2 below, which are novel analogs of Δ⁹-tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), are also available by the synthetic routes herein described and are part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs.

These cannabinoids 2 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is H, CO₂H and its pharmaceutically acceptable salts,         CO₂R^(C), CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, C₃ to C₆ cycloalkyl,         allyl, benzyl, substituted benzyl or 2-phenylethyl; or         NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or         piperidinyl each optionally substituted by one or two hydroxyl         groups or hydroxymethyl groups with the exception that the         hydroxyl groups cannot be on the carbon bearing the heterocyclic         ring nitrogen or the heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl;     -   r are independently 0, 1, 2, 3, 4, 5 or 6;

The aforementioned novel cannabinoids with the limited formulae 2 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs for the treatment or prevention of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 2 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), endocannabinoids or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

The cannabinoids 2 below, which are also novel analogs of Δ⁹-tetrahydrocannabinol (7) and tetrahydrocannabivarin (9), are also available by the synthetic routes herein described and are part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs. These cannabinoids 2 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(A) is CONHR^(D), CONR^(D)R^(E);     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(C) is C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, C₃ to C₆         cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl;     -   q is 0, 1, 2, 3, 4, 5 or 6;     -   R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl,         benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆         alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl, allyl, benzyl, substituted         benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl,         pyrrolidinyl, morpholinyl or piperidinyl each optionally         substituted by one or two hydroxyl groups or hydroxymethyl         groups with the exception that the hydroxyl groups cannot be on         the carbon bearing the heterocyclic ring nitrogen or the         heterocyclic ring oxygen with morpholine;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(r)C₃ to C₆ cycloalkyl.     -   r are independently 0, 1, 2, 3, 4, 5 or 6.

The aforementioned novel cannabinoids with the limited formulae 2 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12), endocannabinoids or Nabilone (16) and/or other drugs for the treatment or prevention of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with the limited formulae 2 above either alone or admixed in combination with known cannabinoids such as but not limited to Δ⁹-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) or Nabilone (16) and/or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids and/or other drugs in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

The dioxinone resorcylate derivatives 5 below, which are intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 5 have the formula:

-   -   wherein:     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂;     -   R^(B) is H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl         or double branched C₄ to C₁₀ alkyl in each case optionally         substituted by one or two hydroxyl groups or optionally         substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆         cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl optionally         substituted by a C₁ to C₈ alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

The dioxinone derivatives 6 below, which are intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These dioxinone derivatives 6 have the formula:

-   -   wherein     -   R¹ is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   R² is H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl,         (CH₂)_(m)—OR³;     -   n are independently 0, 1 or 2;     -   m are independently 1 or 2;     -   R³ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃ or CH(CH₃)₂; R^(B) is H or C₁ to         C₂ alkyl, linear or branched C₃ to C₁₀ alkyl or double branched         C₄ to C₁₀ alkyl in each case optionally substituted by one or         two hydroxyl groups or optionally substituted by one or more         fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F),         or C₃ to C₆ cycloalkyl optionally substituted by a C₁ to C₈         alkyl;     -   o is 0, 1, 2, 3, 4, 5 or 6;     -   p is 1, 2, 3, 4, 5 or 6;     -   R^(F) is C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl;     -   Rα and Rβ are independently C₁ to C₆ alkyl or optionally         substituted aryl or Rα and Rβ in combination are (CH₂)_(s);     -   s is 4, 5 or 6.

EXAMPLES Example 1: (1R,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (6, R¹=R²=Rα=Rβ=CH₃)

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol, 1 equiv.) and 4-dimethylaminopyridine (6.0 g, 50 mmol, 1 equiv.) were sequentially added to a solution of 2-phenyl-1,3-dioxane-4,6-dione (9.6 g, 50 mmol, 1 equiv.) in anhydrous dichloromethane (0.5 L). After five minutes, 2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (9.4 g, 50 mmol, 1 equiv.) was added in one portion. The reaction mixture was stirred for 17 hours at room temperature. After this period, water (0.5 L) was added and the organic fraction separated. The organic phase was washed with 1M HCl (2×0.5 L) and brine (0.5 L). The washed organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was immediately dissolved in anhydrous toluene (0.5 L), and (1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (4) (3.9 g, 25 mmol, 0.5 equiv.) was added as drops. The solution was heated to 55° C. and the temperature was maintained for three hours. Once the starting material had been consumed, the solution was concentrated under reduced pressure. The crude reaction product was purified by flash column chromatography (EtOAc:pentane; 2:20 to 4:20), providing the title compound as a colorless oil (4.3 g, 12 mmol, 48%): ¹H NMR (400 MHz, CDCl₃) δ major isomer 5.46 (dq, J=8.7, 2.1 Hz, 1H), 5.40-5.30 (m, 2H), 4.78 (q, J=1.6 Hz, 1H), 4.74 (dt, J=1.9, 0.9 Hz, 1H), 3.49 (s, 2H), 3.47 (s, 2H), 2.37-2.26 (m, 1H), 2.15-2.02 (m, 1H), 2.02-1.90 (m, 1H), 1.79-1.73 (m, 2H), 1.71 (t, J=1.0 Hz, 16H), 1.70-1.66 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ mixture of isomers 195.7, 166.2, 163.8, 160.6, 145.5, 140.2, 120.3, 118.8, 112.3, 111.5, 107.5, 97.2, 96.6, 92.4, 73.6, 72.4, 69.5, 61.8, 49.6, 46.9, 46.6, 44.2, 39.6, 39.5, 29.8, 26.3, 26.2, 25.1, 23.3, 19.8, 14.2; IR (neat) 2937, 1720, 1639, 1375, 1250, 1201, 1014, 901; HRMS (ES−) m/z calculated for C₂₀H₂₅O₆ [M-H]⁺ 361.1651, found 361.1651; R_(f) 0.2 (EtOAc:pentane; 4:20) UV/Vanillin.

Example 2: (1R,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxooctanoate

Pyridine (1.2 mL, 14 mmol, 2.0 equiv) and MgCl₂ (0.66 g, 6.9 mmol, 1.0 equiv) were added to a solution of (1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (6, R¹=R²=Rα=Rβ=CH₃) (2.5 g, 6.9 mmol, 1.0 equiv) in anhydrous dichloromethane (50 mL) cooled to 0° C. Hexanoyl chloride (1.3 g, 10 mmol, 1.5 equiv) was added dropwise, and the mixture was stirred for one hour. The cooling bath was removed and the mixture was stirred for a further two hours. Saturated aqueous NH₄Cl (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3×50 mL). The organic extracts were washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (EtOAc:pentane; 2:20) to furnish the title compound as a colorless oil (2.9 g, 6.3 mmol, 91%): NMR (400 MHz, CDCl₃) δ 5.60 (dp, J=8.6, 2.1 Hz, 1H), 5.40-5.26 (m, 2H), 4.84-4.73 (m, 2H), 3.66 (s, 2H), 2.74-2.56 (m, 2H), 2.42-2.32 (m, 2H), 2.20-1.94 (m, 3H), 1.40-1.21 (m, 7H), 0.97-0.87 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 198.4, 192.4, 166.4, 165.5, 161.0, 145.8, 140.1, 120.4, 112.3, 109.1, 107.3, 96.6, 73.2, 47.0, 42.9, 37.6, 31.7, 31.4, 29.9, 26.8, 25.9, 24.6, 23.3, 22.6, 22.4, 19.9, 14.1; IR (neat) 2933, 1732, 1702, 1639, 1390, 1375, 1271, 1202, 1068, 899, 755; HRMS (ES−) m/z calculated for C₂₆H₃₅O₇ [M-H]⁺ 459.2383, found 459.2390; R_(f) 0.4 (EtOAc:pentane; 2:20) UV/Vanillin.

Example 3: 7-Hydroxy-2,2-dimethyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (4, R¹=R²=Rα=Rβ=CH₃, R^(B)=C₅H₁₁)

Tri(2-furyl)phosphine (46 mg, 0.2 mmol, 0.2 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, 0.05 equiv.) were sequentially added to a solution of (1R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-yl 2-(2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetyl)-3-oxooctanoate (0.46 g, 1 mmol, 1 equiv.) in THF (10 mL) cooled to 0° C. The mixture was immediately allowed to warm to room temperature. After three hours, 0.5M CsOAc in iso-propanol (6 mL, 3 mmol, 3 equiv.) was added dropwise, and the reaction mixture was stirred for a further 72 hours. The reaction was quenched with 10% aqueous citric acid (10 mL), the biphasic solution was separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The organic extracts were combined and washed with brine (30 mL). The washed organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane:pentane; 1:1) to provide the title compound as a white solid (128 mg, 0.32 mmol, 32%): ¹H NMR (400 MHz, CDCl₃) δ 6.45 (s, 1H), 6.41 (s, 1H), 5.48 (s, 1H), 4.57-4.51 (m, 1H), 4.41 (s, 1H), 3.91-3.82 (m, 1H), 2.99 (t, J=7.7 Hz, 2H), 2.42 (td, J=11.4, 10.9, 3.8 Hz, 1H), 2.24 (t, J=13.0 Hz, 1H), 2.11 (ddd, J=15.5, 5.1, 2.6 Hz, 1H), 1.86-1.76 (m, 4H), 1.69-1.65 (m, 5H), 1.60 (d, J=14.1 Hz, 6H), 1.34 (pd, J=6.8, 3.9 Hz, 4H), 0.88 (tq, J=7.3, 2.6, 2.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 160.8, 156.4, 148.3, 146.4, 146.4, 123.5, 115.1, 113.9, 112.5, 104.7, 104.4, 46.4, 35.6, 34.5, 32.0, 30.6, 30.4, 28.2, 26.3, 24.9, 23.8, 22.7, 14.2; IR (neat) 3271, 2926, 1693, 1604, 1587, 1418, 1287, 1129, 1052; HRMS (ES−) m/z calculated for C₂₅H₃₃O₄ [M-H]⁺ 397.2379, found 397.2386; R_(f) 0.3 (Et₂O:pentane; 2:20) UV/Vanillin.

Example 4: Cannabidiol (11)

Aqueous 6 M NaOH (4 mL) was purged with nitrogen for five minutes in a sealable reaction vial. A nitrogen purged solution of 7-hydroxy-2,2-dimethyl-8-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (80 mg, 0.20 mmol) in methanol (4 mL) was added to the aqueous solution. The reaction vial was sealed and the solution was heated to 120° C. for five hours. The reaction solution was added to vigorously stirring 10% aqueous citric acid (10 mL) and Et₂O (10 mL). After five minutes, the layers were separated and the aqueous layer was extracted with Et₂O (3×10 mL). The ether extracts were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Et₂O:pentane; 1:20 to 2:20) providing the cannabidiol (11) as an white solid (38 mg, 0.12 mmol, 60%): ¹H NMR (400 MHz, MeOD) δ 6.07 (s, 2H), 5.28 (dq, J=2.3, 1.3 Hz, 1H), 4.49-4.39 (m, 2H), 3.96-3.88 (m, 1H), 2.90 (td, J=10.2, 5.5 Hz, 1H), 2.41-2.33 (m, 2H), 2.20 (dd, J=12.5, 6.4 Hz, 1H), 1.99 (dd, J=17.0, 3.5 Hz, 1H), 1.73 (ddd, J=8.6, 6.8, 2.8 Hz, 2H), 1.67 (dt, J=2.5, 1.1 Hz, 3H), 1.63 (t, J=1.1 Hz, 3H), 1.54 (ddd, J=14.7, 8.4, 6.7 Hz, 2H), 1.37-1.24 (m, 5H), 0.89 (t, J=7.0 Hz, 3H); ¹³C NMR (101 MHz, MeOD) δ 157.5, 150.3, 142.7, 134.3, 127.3, 116.0, 110.5, 108.3, 108.3, 46.4, 37.5, 36.6, 32.6, 32.0, 31.7, 30.8, 23.7, 23.6, 19.5, 14.4; R_(f) 0.3 (Et₂O:pentane; 1:20) UVKMnO₄.

Example 5: Δ⁹-Tetrahydrocannabinol (7)

Cannabidiol (11) (40 mg, 0.12 mmol) in dichloromethane (1 mL) was cooled to −10° C. An ice-cooled solution of BF₃.2Et₂O in dichloromethane (1.2 mL, 0.12 mmol, 0.1 M) was added as drops over 20 minutes. The reaction mixture was stirred for a further 40 minutes at 20° C. It was diluted with diethyl ether (5 mL) and a saturated solution of NaHCO₃ (5 mL) was added dropwise. The layers were separated, and the aqueous fraction was extracted with diethyl ether (3×5 mL). The combined organic fractions were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (5% diethyl ether in pentane) to give trans-Δ⁹-tetrahydrocannabinol (7) tetrahydrocannabinol (31 mg, 0.99 mmol, 83%): ¹H NMR (400 MHz, CD₃OD) δ 6.43 (app. pent, J=1.7 Hz, 1H), 6.16 (d, J=1.7 Hz, 1H), 6.07 (d, J=1.7 Hz, 1H), 3.15 (d, J=11.0 Hz, 1H), 2.44-2.37 (m, 2H), 2.15 (d, J=8.6 Hz, 2H), 2.00-1.91 (m, 1H), 1.66 (dq, J=2.4, 1.1 Hz, 3H), 1.60-1.24 (m, 6H), 1.37 (s, 3H), 1.05 (s, 3H), 0.90 (t, J=7.0 Hz, 4H); ¹³C NMR (100 MHz, CD₃OD) δ 157.2, 155.8, 143.3, 133.5, 126.2, 110.4, 109.7, 108.4, 77.9, 47.5, 36.6, 35.2, 32.7, 32.3, 32.1, 28.0, 26.3, 23.6, 23.6, 19.4, 14.4; IR (neat) 3383, 2952, 2924, 2855, 1621, 1577, 1423, 1233, 1181, 1049, 1036, 835

HRMS (ES+) m/z calculated for C₂₁H₃₁O₂ [M-H]⁺ 315.2319, found 315.2319; Rf 0.21 (Et₂O:pentane; 1:20) UV/KMnO₄.

Example 6: Bioassay of Synthetic Cannabidiol (11)

TRPV channel activity was utilized to assess and show that the biological activity of the synthesized cannabidiol (11, CBD), described herein, was the same as cannabidiol reference standard, thus further confirming the identity of the synthesized cannabidiol (11, CBD). TRPV channels including TRPV1 have been shown to mediate effects of cannabinoids (H. Turner, D. Chueh, T. Ortiz, A. J. Stokes and A. L. Small-Howard, Therapeutics in Parkinson's Disease: Promise and Paradox, Journal of Herbs, Spices & Medicinal Plants, 2017, volume 23, 2017, pages 231-248) and (B. Costa, G. Giagnoni, C. Franke, A. E. Trovato and M. Colleoni, Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation, British Journal of Pharmacology, 2004, volume 143, pages 247-250) and capsaicin, also useful as a reference standard (I. Díaz-Franulic, J. Caceres-Molina, R. V. Sepulveda, F. Gonzalez-Nilo, R. Latorre, Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1. Molecular Pharmacology, 2016, volume 90, pages 300-308) HEK 293 cells with TRPV1 channels have been used as model systems (P. Geppetti and M. Trevisani, Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function, British Journal of Pharmacology, 2004, volume 141, pages 1313-1320);

The results presented in FIGS. 1A-1D show that the sample of cannabidiol (11, CBD) synthesized by the process described herein and a reference standard cannabidiol (sourced from Sigma Aldrich) have the same “biological finger print” and dose response on TRPV 1 channels as shown using the analytical method below and as previously described (J. S. Horton, T. Shiraishi, N. Alfulaii, A. L. Small-Howard, H. C. Turner, T. Kurokawa, Y. Mori and A. J Stokes, TRPV1 is a component of the atrial natriuretic signaling complex, and using orally delivered antagonists, presents a valid therapeutic target in the longitudinal reversal and treatment of cardiac hypertrophy and heart failure, Channels (Austin), 2019, volume 13, pages 1-16).

Cell Culture

HEK TRexTRPV1 cultured in DMEM, 10% Fetal Bovine Serum, 2 mM L-glutamine, 10 microgramg/ml Blasticidin (Calbiochem, San Diego Calif.), 400 mg/ml Zeocin (InvivoGen, San Diego Calif.), followed by inducing indicated transgene expression using 1 microgram/ml Tetracycline for 16-24 hrs. Comparisons made to untransfected HEK cells or HEKTRexTRPV1 with or without induction.

Calcium Assay

Cells washed and incubated with 0.2 micromolar Fluo-4 [54] for 30 minutes at 37° C. in a standard modified Ringer's solution of the following composition (in mM): NaCl 145, KCl 2.8, CsCl 10, CaCl₂ 10, MgCl₂ 2, glucose 10, Hepes-NaOH 10, pH 7.4, 330 mOsm. Cells transferred to 96-well plates at 50,000 cells/well and stimulated as indicated. Calcium signals acquired using a Flexstation 3 (Molecular Devices, Sunnydale, USA). Data are analyzed according to the methods in I. Díaz-Franulic, J. Caceres-Molina, R. V. Sepulveda, F. Gonzalez-Nilo, R. Latorre, Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1, Molecular Pharmacology, 2016, volume 90, pages 300-8.

Dose response and comparison in HEK-TRPV1 cells between the Cannabidiol (11, CBD) synthesized according to the described method (identified in FIGS. 1A-1D as “CBD, Synth”) to Sigma-sourced CBD (CAS No. 13956-29-1; identified in FIGS. 1A-1D as “CBD, Sigma”) is depicted in FIGS. 1A-1D. Normal saline reference standard is identified as “NS” in FIGS. 1A-1D.

All samples tested under the identical conditions: Fluo-4 loaded cells in 1 mM external calcium chloride; 0-20 seconds baseline; at 20 seconds, compound added. (uM=micromolar). 

What is claimed is:
 1. A process for the preparation of substantially pure product compounds of the formulae 1 and 2 or as an enantiomer of compounds of the formulae 1 or 2 or as a racemic mixture of enantiomers of compounds of the formulae 1 or 2:

wherein: R¹ is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, (CH₂)_(m)—OR³; R² is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, (CH₂)_(m)—OR³; each n is independently an integer selected from 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃ and CH₂CH₂CH₃ or CH(CH₃)₂; R^(A) is selected from the group consisting of H and CO₂H and pharmaceutically acceptable salts thereof, CO₂R^(C), CONHR^(D) and CONR^(D)R^(E); R^(B) is selected from the group consisting of H, C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl or double branched C₄ to C₁₀ alkyl optionally substituted by one or two hydroxyl groups, one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), C₃ to C₆ cycloalkyl optionally substituted by a C₁ to C₈ alkyl; o is an integer selected from 0-6; p is an integer selected from 1-6; R^(C) is selected from C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; q is an integer selected from 0-6; R^(D) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; R^(E) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R^(F) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl; wherein each r is independently an integer selected from 0-6; said process comprising: providing a first intermediate selected from the group consisting of a compound of formula 3 or formula 6

in which when one or both of R¹ and R² is (CH₂)_(m)—OH, any hydroxyl group is protected; sequentially treating the first intermediate with (a) an acylating reagent R^(B)COY in which any hydroxyl group or groups in R^(B) are protected in the presence of a first base 17 in the presence of a Lewis acid 18, (b) a palladium catalyst 19 with optional additional ligands 20, and (c) silica or an alternative equivalent solid reagent or a second base 21 followed by a Brønsted or Lewis acid 22, or a base alone and optional deprotection to provide the second intermediate 4:

and treating the second intermediate 4 under hydrolysis conditions with optional decarboxylation; or treating the second intermediate 4 under transesterification or by amide formation conditions with optional deprotection as appropriate to provide a compound of the formula 1; or when one or more of the hydroxyl groups in R¹, R², wherein R² is (CH₂)_(m)—OH, or R^(B) are protected, treating the first intermediate 4 with a Lewis acid 23 to provide intermediate 5:

and hydrolyzing the resultant with optional decarboxylation or by transesterification or by amide formation with optional deprotection, to provide a compound of formula 2; wherein: Y is halogen or R^(B)COY is an alternative reactive electrophilic acylating agent; Rα and Rβ are independently selected from C₁ to C₆ alkyl and optionally substituted aryl, or Rα and Rβ combine to form (CH₂)_(s); wherein: s is an integer selected from 4-6.
 2. The process according to claim 1, wherein Y is a halide; Rα and Rβ are both methyl; the first base 17 is pyridine; the first Lewis acid 18 is selected from the group consisting of magnesium chloride, lithium chloride and zinc chloride; the silyl protecting groups, if present, are independently selected from the group consisting of t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl and tri-iso-propylsilyl protecting groups.
 3. The process according to claim 1, wherein the palladium catalyst 19 is derived from a palladium(II) complex in the presence of a phosphine as ligand 20; the second base 21 is selected from the group consisting of cesium acetate, cesium carbonate and potassium carbonate; the Brønsted or Lewis acid 22, if used, is acetic acid or hydrogen chloride.
 4. The process according to claim 1, wherein the Lewis acid 23 is a derivative of a metal or metalloid or an inorganic solid, or is replaced by a Brønsted acid or any combination of such a Lewis acid and Brønsted acid, Lewis acid and inorganic solid, Brønsted acid and inorganic solid or Lewis acid, Brønsted acid and inorganic solid; the hydroxyl protecting group or groups, if present, are silyl protecting groups.
 5. The process according to claim 1, wherein Y is a chloride; the first base 17 is pyridine; the first Lewis acid 18 is magnesium chloride; the palladium catalyst 19 is tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] in the presence of tri-2-furylphosphine as ligand 20; the second base 21 is cesium acetate.
 6. The process according to claim 2, wherein Y is a chloride; the first base 17 is pyridine; the first Lewis acid 18 is magnesium chloride.
 7. The process according to claim 3, wherein the palladium catalyst 19 is tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] in the presence of tri-2-furylphosphine as ligand 20; the second base 21 is cesium acetate.
 8. The process according to claim 1, wherein the product compound is a compound of the formula 1:

wherein: R¹ is selected from the group consisting of C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; R² is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; each n is independently an integer from 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CH(CH₃)₂; R^(A) is selected from the group consisting of H, CO₂H and its pharmaceutically acceptable salts, CO₂R^(C), CONHR^(D), and CONR^(D)R^(E); R^(B) is selected from the group consisting of H, C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl, and double branched C₄ to C₁₀ alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl or optionally substituted by a C₁ to C₈ alkyl; o is an integer 0-6; p is an integer 1-6; R^(C) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer 0-6; R^(D) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R^(E) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl, each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R^(F) is C₁ to C₆ alkyl or (CH₂)_(r)—C₃ to C₆ cycloalkyl; each r is independently an integer 0-6.
 9. The process according to claim 1, wherein the product compound is a compound of the formula 1:

wherein: R¹ is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; R² is selected from the group consisting of C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; each n is independently an integer 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CH(CH₃)₂; R^(A) is selected from the group consisting of H, CO₂H and its pharmaceutically acceptable salts, CO₂R^(C), CONHR^(D), and CONR^(D)R^(E); R^(B) is selected from the group consisting of H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl and double branched C₄ to C₁₀ alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl or optionally substituted by a C₁ to C₈ alkyl; o is an integer 0-6; p is an integer 1-6; R^(C) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer 0-6; R^(D) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R^(E) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R^(F) is C₁ to C₆ alkyl or (CH₂)_(r)—C₃ to C₆ cycloalkyl; each r is independently an integer 0-6.
 10. The process according to claim 1, wherein the product compound is a compound of the formula 1:

wherein: R¹ is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; R² is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; each n is independently an integer 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CH(CH₃)₂; R^(A) is CONHR^(D) or CONR^(D)R^(E); R^(B) is selected from the group consisting of H or C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl and double branched C₄ to C₁₀ alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl or optionally substituted by a C₁ to C₈ alkyl; o is an integer 0-6; p is an integer 1-6; R^(C) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer 0-6; R^(D) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R^(E) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; RF is C₁ to C₆ alkyl or (CH₂)_(r)—C₃ to C₆ cycloalkyl; each r is independently an integer 0-6.
 11. The process according to claim 1, wherein the product compound is a compound of the formula 2:

wherein: R¹ is selected from the group consisting of C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; R² is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; each n is independently an integer 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CH(CH₃)₂; R^(A) is selected from the group consisting of H, CO₂H and its pharmaceutically acceptable salts, CO₂R^(C), CONHR^(D), and CONR^(D)R^(E); R^(B) is selected from the group consisting of H, C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl and double branched C₄ to C₁₀ alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl or optionally substituted by a C₁ to C₈ alkyl; o is an integer 0-6; p is an integer 1-6; R^(C) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer 0-6; R^(D) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R^(E) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR^(D)R^(E) is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R^(F) is C₁ to C₆ alkyl or (CH₂)_(r)—C₃ to C₆ cycloalkyl; each r is independently an integer 0-6.
 12. The process according to claim 1, wherein the product compound is a compound of the formula 2:

R¹ is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and(CH₂)_(m)—OR³; R² is selected from the group consisting of C₂ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; each n is independently an integer 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CH(CH₃)₂; R^(A) is selected from the group consisting of H, CO₂H and its pharmaceutically acceptable salts, CO₂R^(C), CONHR^(D), and CONR^(D)R^(E); R^(B) is selected from the group consisting of H, C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl and double branched C₄ to C₁₀ alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl or optionally substituted by a C₁ to C₈ alkyl; o is an integer 0-6; p is an integer 1-6; R^(C) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer 0-6; R^(D) is C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R^(E) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR^(D)R^(E) is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R^(F) is C₁ to C₆ alkyl or (CH₂)_(r)—C₃ to C₆ cycloalkyl; each r is independently an integer 0-6.
 13. The process according to claim 1, wherein the product compound is a compound of the formula 2:

wherein: R¹ is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; R² is selected from the group consisting of H, C₁ to C₆ alkyl, (CH₂)_(n)—C₃ to C₆ cycloalkyl, and (CH₂)_(m)—OR³; each n is independently an integer 0-2; each m is independently 1 or 2; R³ is selected from the group consisting of H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CH(CH₃)₂; R^(A) is CONHR^(D) or CONR^(D)R^(E); R^(B) is selected from the group consisting of H, C₁ to C₂ alkyl, linear or branched C₃ to C₁₀ alkyl and double branched C₄ to C₁₀ alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH₂)_(o)—C₃ to C₆ cycloalkyl, (CH₂)_(p)—OR^(F), or C₃ to C₆ cycloalkyl or optionally substituted by a C₁ to C₈ alkyl; o is an integer 0-6; p is an integer 1-6; R^(C) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(q)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer 0-6; R^(D) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; and R^(E) is selected from the group consisting of C₁ to C₆ alkyl, (CH₂)_(r)—C₃ to C₆ cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR^(D)R^(E) is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl, each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups, with the proviso that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R^(F) is C₁ to C₆ alkyl or (CH₂)_(r)—C₃ to C₆ cycloalkyl; each r is independently an integer 0-6.
 14. The process according to claim 1, wherein the product compounds of the formulae 1 or 2 are selected from the group consisting of: 